For more than 20 years, the dopamine hypothesis has been the dominating hypothesis for the pathophysiology of schizophrenia. It states that the symptoms of schizophrenia are related to increased central dopaminergic transmission. The hypothesis was supported when increased densitites of D2-dopamine receptors were demonstrated in post-mortem brains from patients with schizophrenia. Increased densities, however, may have been caused by neuroleptic drug treatment during life-time. Using positron emission Tomography (PET) and 11C- labelled radioligands it is possible to test the hypothesis in young never neuroleptic-treated patients with schizophrenia. One research group used a kinetic model and the radioligand 11C-NMSP and found a two- to three-fold elevation in D2-dopamine receptor densities in young drug-naive schizophrenic patients. The present applicant used 11C- raclopride and an equilibrium model and found no difference. For future schizophrenia research it is of key interest to resolve this discrepancy. The first specific aim of the present continuation project is to compare the two quantitative methods in the same individuals and to replicate the study with 11C-NMSP in Swedish drug-naive schizophrenic subjects. A second aim is to examine if longterm neuroleptic drug treatment causes an increase in the density of central D2-dopamine receptors in man. Using PET it has been demonstrated that clinical doses of neuroleptics representing all the chemical classes used today, block-D2-dopamine receptors to a high degree. The individual response to neuroleptic drug treatment is highly variable and in some patients severe side effects are recorded. In order to reduce the risk of side effects the titration of the minimal antipsychotic dose in each patient is a necessity. There is need for useful measures to guide the dose-finding procedure. A specific aim of the present project is to relate D2-dopamine receptor occupancy for the classical antipsychotic haloperidol and for the atypical antipsychotic clozapine to antipsychotic effect and to extrapyramidal side effect. It may be possible to define a dose-response relationship or a "threshold occupancy" for the antipsychotic effect. In this way a principally new measure could be obtained to guide the clinical selection of optimal doses for antipsychotic drug treatment. Additional aims of the application is to study D2-receptor occupancy during treatment with depot neuroleptics and with very high doses of neuroleptics.